Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation

Mohamed El-Far, Petronela Ancuta, Jean Pierre Routy, Yuwei Zhang, Wendy Bakeman, Rebeka Bordi, Sandrina DaFonseca, Elias A. Said, Annie Gosselin, Tévy Suzy Tep, Quentin Eichbaum, Julien van Grevenynghe, Olivier Schwartz, Gordon J. Freeman, Elias K. Haddad, Nicolas Chomont, Rafick Pierre Sékaly

Research output: Contribution to journalArticle

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Abstract

CTLA-4 is a negative regulator of T-cell receptor-mediated CD4+ T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4+ T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4+ T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4+ T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4+CTLA-4+ T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3+CD4–CD8– [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4+ and CTLA-4– subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4+ cells. Together, these results suggested that HIV-1 preferential infection of CD4+CTLA-4+ T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA- 4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.

Original languageEnglish
Pages (from-to)1463-1477
Number of pages15
JournalJournal of General Virology
Volume96
DOIs
Publication statusPublished - 2015

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HIV-1
T-Lymphocytes
HIV
Virus Diseases
Down-Regulation
Infection
Virus Activation
DNA
Immune System Diseases
Viral DNA
T-Cell Antigen Receptor
Disease Progression
Up-Regulation
Biomarkers

ASJC Scopus subject areas

  • Virology

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Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation. / El-Far, Mohamed; Ancuta, Petronela; Routy, Jean Pierre; Zhang, Yuwei; Bakeman, Wendy; Bordi, Rebeka; DaFonseca, Sandrina; Said, Elias A.; Gosselin, Annie; Tep, Tévy Suzy; Eichbaum, Quentin; van Grevenynghe, Julien; Schwartz, Olivier; Freeman, Gordon J.; Haddad, Elias K.; Chomont, Nicolas; Sékaly, Rafick Pierre.

In: Journal of General Virology, Vol. 96, 2015, p. 1463-1477.

Research output: Contribution to journalArticle

El-Far, M, Ancuta, P, Routy, JP, Zhang, Y, Bakeman, W, Bordi, R, DaFonseca, S, Said, EA, Gosselin, A, Tep, TS, Eichbaum, Q, van Grevenynghe, J, Schwartz, O, Freeman, GJ, Haddad, EK, Chomont, N & Sékaly, RP 2015, 'Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation', Journal of General Virology, vol. 96, pp. 1463-1477. https://doi.org/10.1099/vir.0.000065
El-Far, Mohamed ; Ancuta, Petronela ; Routy, Jean Pierre ; Zhang, Yuwei ; Bakeman, Wendy ; Bordi, Rebeka ; DaFonseca, Sandrina ; Said, Elias A. ; Gosselin, Annie ; Tep, Tévy Suzy ; Eichbaum, Quentin ; van Grevenynghe, Julien ; Schwartz, Olivier ; Freeman, Gordon J. ; Haddad, Elias K. ; Chomont, Nicolas ; Sékaly, Rafick Pierre. / Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation. In: Journal of General Virology. 2015 ; Vol. 96. pp. 1463-1477.
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abstract = "CTLA-4 is a negative regulator of T-cell receptor-mediated CD4+ T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4+ T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4+ T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4+ T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4+CTLA-4+ T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3+CD4–CD8– [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4+ and CTLA-4– subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4+ cells. Together, these results suggested that HIV-1 preferential infection of CD4+CTLA-4+ T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA- 4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.",
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AU - Routy, Jean Pierre

AU - Zhang, Yuwei

AU - Bakeman, Wendy

AU - Bordi, Rebeka

AU - DaFonseca, Sandrina

AU - Said, Elias A.

AU - Gosselin, Annie

AU - Tep, Tévy Suzy

AU - Eichbaum, Quentin

AU - van Grevenynghe, Julien

AU - Schwartz, Olivier

AU - Freeman, Gordon J.

AU - Haddad, Elias K.

AU - Chomont, Nicolas

AU - Sékaly, Rafick Pierre

PY - 2015

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